Sleep disorders among the elderly are pervasive, yet frequently undiagnosed and untreated. 'Poor sleep'has been associated with a variety of age-related conditions, including reduced cognitive function, depression and mortality. Sleep-wake regulation is a complex process involving environmental influences and genetic predisposing factors and little is known about the effect of circadian gene variants on human sleep function and age-related outcomes. This project will test the hypothesis that genetic variations in circadian pathway genes affect human sleep function and other age-related outcomes. Our specific aims are to test common genetic variants and haplotypes in 21 circadian rhythm and 4 melatonin metabolism genes for association with rest activity rhythms and sleep characteristics as measured by actigraphy, and with cognitive function, depression and mortality in two prospective cohorts of elderly U.S. women and men participating in the SOF and MrOS cohorts. During 2002-2003, wrist actigraphy was recorded in all returning Caucasian and African American SOF participants (n>2600 with DNA collected). During the MrOS sleep visit in 2004-2005, 2,846 Caucasian and African American participants (all with available DNA) completed wrist actigraphy and in-home overnight polysomnography. We are also including all African Americans with available DNA to improve our power to detect genotype associations with mortality, cognitive function and depression. This is one of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world. We are uniquely positioned to examine the role of circadian rhythm and melatonin metabolism gene variants in a large sample. Compared to the cost of recruitment, phenotyping, and DNA collection, which have already been accomplished in >5700 participants, the genotyping cost will be small. The 2003 National Sleep Disorders Research Plan as put forward by The National Center on Sleep Disorders Research calls for an assessment of normal human sleep phenotypes and a full evaluation of "associated genotypes" to define the genetic underpinning of abnormal sleep or altered circadian rhythm profiles. Understanding the underlying causes and consequences of sleep disturbances and cognitive impairments is a high priority in terms of public health. Discovering gene polymorphisms that affect sleep and other age-related outcomes could lead to interventions that have a very significant impact on improving health, safety, and productivity of the elderly population. PUBLIC HEALTH RELEVANCE: This project will test whether genetic variants in the 21 circadian rhythm and 4 melatonin metabolism genes are associated with rest activity rhythms and sleep characteristics (as measured by actigraphy), mortality, cognitive function and depression in older men and women participating in the Study of Osteoporotic Fractures and Osteoporotic Fractures in Men cohorts. These are two of the largest data sets of objective sleep data and associated mental, depression, and health data available in the world and relative to the costs of recruitment and phenotyping, which have already been accomplished, the genotyping cost is small. Discovering genes that affect sleep and age-related outcomes could lead to interventions that have a very significant impact on improving health, quality of life and longevity on the elderly population.